Emerging evidence supports the idea that adolescence is a unique developmental period during which time individuals are more likely to experiment with drugs of abuse and are at greater risk for subsequent addiction. There is a strong correlation between the onset of nicotine addiction at an early age and addiction to alcohol as well as a heightened vulnerability to addiction to either ethanol or nicotine when use is initiated during adolescence. When the brain is exposed to drugs of abuse, adaptive changes take place that contribute to the addictive process. Evidence demonstrates that many drugs alter the expression and activity of two major transcription factors, viz., cAMP response element binding protein (CREB) and AFosB (a truncated form of FosB) and that these alterations lead to the expression of genes thought to mediate the addictive process. Although studies have suggested that CREB and AFosB may represent a common cellular target for the action of addictive drugs, few studies have focused on the cellular consequences of exposure to nicotine and subsequent vulnerability to alcohol, targeting the two most widely used/abused and coabused compounds in the adolescent population.